消化道由其內生之屏障生理功能與刺激物、致癌物與微生物相產生複雜的癌細胞免疫平衡。免疫檢查點抑制療法 (ICPi) 能增強免疫誘發癌細胞死亡。然而，大多數消化道癌患者均未能成功誘導出滿意的治療效應，因此了解腫瘤源生標靶與免疫治療顯得相當重要。本論文之目的旨為探索與驗證消化道癌中抗癌免疫監測作用下腫瘤源生標靶與免疫微環境的關係與生物機制。首先，本文中觀察到膽管癌腫瘤表面之Globo H與PD-L1之關聯並與抑制性腫瘤浸潤免疫細胞 (Timc) 之豐富度相關。再者，帶有N6-腺苷酸甲基化調控之胃癌透過增強PD-L1表現促進免疫脫逃作用，特別是HER2過表現之胃癌。再者，我們發現合併肝細胞膽管癌中Timc和B型肝炎感染與較佳預後有關，而較豐富的Timc與B型肝炎病毒感染之腫瘤較似於肝細胞癌而非膽管癌。最後，我們發現帶有驅動基因變異例如RET之多種消化道腫瘤針對ICPi療法有較差的療效。總結來說，腫瘤源生標靶能改變消化道腫瘤之免疫微環境，本文所發現能提供決定抗癌免疫療法的路徑並可能將免疫抗性高之”冷腫瘤”轉變為活性高之”熱腫瘤”，結果或可提供困難治療之消化道癌症一項較佳的治療策略。

Digestive tract is known for its inherent physiological function as a barrier to stimulants, carcinogens or microbiomes and involves delicate interplay of cancer immune equilibrium. Immune checkpoint inhibitor (ICPi) therapies enhance the immunogenic cell death. However, it fails to generate a satisfactory response for most patients and highlights the research demand for elucidating tumor-derived targets in immunotherapy. The aim of the dissertation was to explore and validate tumor-derived targets and their correlations with immune microenvironment and biological properties concerning antitumor immune surveillance in digestive tract cancers. In the dissertation, we first observed tumor Globo H and its association with surface programmed death ligand-1 (PD-L1) and enrichment of suppressive tumor infiltrating immune cells (Timcs) in cholangiocarcinoma. Secondly, we observed that m6A regulation potentiated immune evasive condition via up-regulating PD-L1 expression predominantly in HER2-enriched gastric cancer. In addition, we discovered that Timcs and hepatitis B virus (HBV) infection were relevant prognostic factors in combined hepatocellular cholangiocarcinoma (cHCC-CCA). Timcs-enriched and HBV-infected tumors resembled primary HCC but not CCA. Finally, we disclosed that genomic driver alterations, such as RET, correlated with a blunted response to ICPi therapy across several digestive tract cancers. In conclusion, tumor-derived targets affect the immune microenvironment in digestive tract cancers. The information provides access to decipher antitumor immunotherapy and transform the immune evasive “cold” tumors into the reactive “hot” ones. It may optimize the therapeutic benefits in difficult-to-treat digestive tract cancers.

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